chr9-127818221-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM5PP3_StrongBS2

The NM_001114753.3(ENG):c.1585C>T(p.Arg529Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R529H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 2.73

Publications

3 publications found

Variant links:

Genes affected

ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ENG Gene-Disease associations (from GenCC):

telangiectasia, hereditary hemorrhagic, type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
hereditary hemorrhagic telangiectasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
juvenile polyposis syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENG links:

ENSG00000225032 (HGNC:):

ENSG00000225032 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-127818220-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 213212.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3 link	c.1585C>T	p.Arg529Cys	missense_variant	Exon 12 of 15	ENST00000373203.9	NP_001108225.1	P17813-1Q96CG0A0A024R878
ENG	NM_000118.4 link	c.1585C>T	p.Arg529Cys	missense_variant	Exon 12 of 14		NP_000109.1	P17813-2Q5T9B9
ENG	NM_001278138.2 link	c.1039C>T	p.Arg347Cys	missense_variant	Exon 12 of 15		NP_001265067.1	P17813Q96CG0F5GX88B7Z6Y5
LOC102723566	NR_136302.1 link	n.1378-90G>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 link	c.1585C>T	p.Arg529Cys	missense_variant	Exon 12 of 15	1	NM_001114753.3	ENSP00000362299.4		P17813-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251302

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 30, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with features of hereditary hemorrhagic telangiectasia (HHT), including one patient who harbored another potentially disease-causing variant in the ACVRL1 gene (McDonald et al., 2011; Mallet et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as this variant may have an impact on cell surface localization (Mallet et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 583144; ClinVar); This variant is associated with the following publications: (PMID: 28564608, 30763665, 31727138, 25312062, 21158752) -

May 20, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary hemorrhagic telangiectasia

Pathogenic:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 529 of the ENG protein (p.Arg529Cys). This variant is present in population databases (rs745316066, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 21158752; internal data). ClinVar contains an entry for this variant (Variation ID: 583144). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ENG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ENG function (PMID: 25312062). This variant disrupts the p.Arg529 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16752392, 17384219, 18495117, 22991266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Sep 14, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the ENG gene demonstrated a sequence change, c.1585C>T, in exon 12 that results in an amino acid change, p.Arg529Cys. This sequence change has been previously described in an individual with multiple pulmonary arteriovenous malformation (AVMs) and epistaxis in conjunction with an exon 4 deletion in the ACVRL1 gene (PMID: 21158752). Family members were unavailable for clinical evaluation or co-segregation study. This variant showed partial cellular surface localization, induced partial BMP9 binding and partial BMP9 response (~ 60% of the wildtype) (PMID: 25312062). This sequence change has been described in three heterozygous individuals in the gnomAD database which corresponds to the overall low population frequency of 0.0011% (dbSNP rs745316066). The p.Arg529Cys change affects a highly conserved amino acid residue located in a domain of the ENG protein that is known to be functional. The p.Arg529Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Arg529Cys change remains unknown at this time. -

Telangiectasia, hereditary hemorrhagic, type 1

Uncertain:1

Dec 10, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ENG c.1585C>T; p.Arg529Cys variant (rs745316066), is reported in individuals with suspected HHT (Mallet 2015, McDonald 2011), and is reported in ClinVar (Variation ID: 583144). However, in one individual, the deletion of ACVRL1 exon 4 was also identified by multiplex ligation-dependent probe amplification (MLPA) (McDonald 2011). Functional analyses of the p.Arg529Cys variant protein shows partially impaired BMP9 binding and response, as well as partially impaired localization (Mallet 2015). Furthermore, a different variant at this codon, p.Arg529His, is reported in the literature in individuals with symptoms of HHT (Bossler 2006, Gedge 2007, Nishida 2012). The p.Arg529Cys variant is found in the general population with a low allele frequency of 0.001% (3/282678 alleles) in the Genome Aggregation Database. The arginine at codon 529 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg529Cys variant is uncertain at this time. REFERENCES Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 27(7):667-75. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn.2007 9(2):258-65. Mallet C et al. Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum Mol Genet. 2015 Feb 15;24(4):1142-54. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 158A(11):2829-34. -

Cardiovascular phenotype

Uncertain:1

Jul 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R529C variant (also known as c.1585C>T), located in coding exon 12 of the ENG gene, results from a C to T substitution at nucleotide position 1585. The arginine at codon 529 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this variant was detected in an individual with multiple pulmonary arteriovenous malformations and epistaxis who also carried a single exon deletion in the ACVRL1 gene (McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). This variant has also been detected in a pulmonary arterial hypertension cohort (Zhu N et al. Genome Med. 2019 11;11(1):69). In a functional study, the protein with this alteration showed approximately 60% surface expression level compared to wild type and approximately 70% of the BMP9-induced luciferase activity; however, the authors comment that the reduced BMP9 response could be the result of the reduced ENG expression in the in vitro system rather than activity changes (Mallet C et al. Hum. Mol. Genet., 2015 Feb;24:1142-54). A disease-causing mutation at the same codon, p.R529H (c.1586G>A), has been described in individuals meeting clinical diagnostic criteria for hereditary hemorrhagic telangiectasia (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;D;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.5

L;.;L

PhyloP100

2.7

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-6.0

D;.;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.66

MutPred

0.86

Gain of catalytic residue at S531 (P = 0.0608);.;Gain of catalytic residue at S531 (P = 0.0608);

MVP

0.95

MPC

0.95

ClinPred

0.99

GERP RS

4.2

Varity_R

0.70

gMVP

0.79

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over